Hereditary Angioedema (HAE) is characterized by recurrent episodes of edema, believed to result from a marked decrease in functional Cl inhibitor (Cl ,INH) . The pathologic changes are primarily due to vascular leakage into the subepithelium. Identification of the actual mediator(s) responsible, however, has thus far eluded investigators. Presently, bradykinin and a cleavage fragment of C2, "C2-kinin", are believed to be the most likely candidates. Recent work in this laboratory has demonstrated that cleavage of a sialoglycoprotein, sgp 120, by kallikrein results in the release of a small molecular weight fragment which is also a potent mediator of vascular permeability. The objective of this project is to identify mediator(s) involved in HAE swelling. Much of our initial work was performed developing a sensitive ELISA that enables us to directly measure trace quantities of small molecular weight fragments released from sgp 120, high molecular weight kininogen (including bradykinin), and C2 from human plasma. Blood is obtained with or without plasma protein inhibitors and the plasma or serum is spun through filters which separate released fragments with a molecular weight of less than 10,000, from larger plasma proteins. These fragments are detected with specific polyclonal or monoclonal antisera. We have observed that sera and plasma obtained from HAE patients are more likely to generate small molecular weight fragments of sgp 120 than those obtained from normal individuals. Furthermore, preliminary studies suggest that plasma obtained from HAE patients during an attack may contain increased levels of the sgp 120 fragments than before or after the attack. To systematically study the release of mediators during an HAE attack, we have designed a protocol, which was approved by the NIAID-CRS, in which HAE patients will be admitted to the Clinical Center for controlled induction of extremity swelling. Blood obtained at established time intervals will be evaluated, using the assay described above, for the presence of small molecular weight fragments released from sgp 120, high molecular weight kininogen, and C2.